Researchers used a transgenic mouse model in which they could increase or decrease the production of HER2 protein to determine how resistance occurs. Increased HER2 resulted in humanlike HER2-positive mammary tumors. Decreased HER2 caused the tumors to shrink, though in approximately two-thirds of the mice, tumors recurred.

Researchers examined tissue samples from original and recurrent tumors using RNA sequencing. They discovered that the recurrent tumors had overactive genes involved in cell division and growth, particularly cyclin D1 and CDK4, which can form a progrowth protein complex.

“We hypothesized that cyclin D1 and CDK4 might also enable tumors to become resistant to HER2-targeted treatments and eventually recur.”

Results from cell cultures and additional mouse experiments suggested that the cyclin D1/CDK4 complex is important in the development of resistance in HER2-positive tumors. The researchers examined abemaciclib, a CDK4 inhibitor, to overcome the resistance. Administration of abemaciclib overcame HER2 inhibitor resistance.

“Finding ways to re-sensitize drug-resistant tumors, to restore their vulnerability to front-line agents, is a critical priority for cancer researchers,” explained Goel.

When researchers added a HER2 inhibitor to abemaciclib, the results were even more pronounced. In addition, abemaciclib administration delayed the recurrence of HER2-positive mammary cancer in mice, as did the administration of both abemaciclib and a HER2 inhibitor, suggesting abemaciclib treatment could help prevent breast cancer recurrence.

“Strikingly, when we added a HER2-targeting drug to abemaciclib, we saw even greater efficacy. This means that abemaciclib restored the cancer cells’ sensitivity to HER2-directed agents,” said Goel.

Clinical trials in the United States and Europe are planned for later this year.